A single amphetamine infusion reverses deficits in dopamine nerve-terminal function caused by a history of cocaine self-administration (2015)

Abstract

There are approximately 1.6 million people who meet the criteria for cocaine addiction in the United States, and there are currently no FDA approved pharmacotherapies. Amphetamine-based dopamine releasing drugs have shown efficacy for reducing the motivation to self-administer cocaine and reducing intake in animals and humans. It is hypothesized that amphetamine acts as a replacement therapy for cocaine through elevation of extracellular dopamine levels.

Using voltammetry in brain slices, we tested the ability of a single amphetamine infusion in vivo to modulate dopamine release, uptake kinetics, and cocaine potency in cocaine naïve animals and after a history of cocaine self-administration (1.5 mg/kg/infusion, fixed-ratio 1, 40 injections/day x 5 days). Dopamine kinetics were measured 1 and 24 hours after amphetamine infusion (0.56 mg/kg, i.v.). Following cocaine self-administration, dopamine release, maximal rate of uptake (Vmax), and membrane-associated dopamine transporter (DAT) levels were reduced, and the DAT was less sensitive to cocaine. A single amphetamine infusion reduced Vmax and membrane DAT levels in cocaine naïve animals, but fully restored all aspects of dopamine terminal function in cocaine self-administering animals.

Here, for the first time, we demonstrate pharmacologically-induced, immediate rescue of deficits in dopamine nerve-terminal function in animals with a history of high dose cocaine self-administration. This observation supports the notion that the DAT expression and function can be modulated on a rapid time-scale and also suggests that the pharmacotherapeutic actions of amphetamine for cocaine addiction go beyond that of replacement therapy.

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